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Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3'-5'/2'-5' linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved treatment. The natural compound silybin (SLN) has versatile hepatoprotective efficacy with negligible adverse effects; however, poor absorption limits its clinical applications. Gut microbiota has been proposed to play a crucial role in the pathophysiology of NAFLD and targeted for disease control. Cyclodextrins, the cyclic oligosaccharides, were documented to have various health benefits with potential prebiotic properties. This study aimed to develop a silybin-2-hydroxypropyl-β-cyclodextrin inclusion (SHβCD) to improve the therapeutic efficacy of SLN and elucidate the mechanisms of improvement. The results showed that SLN formed a 1:1 stoichiometric inclusion complex with HP-β-CD. The solubility of SLN was increased by generating SHβCD, resulting in improved drug permeability and bioavailability. In high-fat diet (HFD)-fed hamsters, SHβCD modulated gut health by restoring the gut microbiota and intestinal integrity. SHβCD showed superior anti-lipid accumulation, antioxidant, and anti-inflammatory effects compared with SLN alone. Transcriptome analysis in the liver tissue implied that the improved inflammation and/or energy homeostasis was the potential mechanism. Therefore, SHβCD may be a promising alternative for the treatment of NAFLD, attributing to the dual functions of HβCD on drug absorption and gut microbial homeostasis.

Ab initio calculations have been carried out to investigate the adsorption, dissociation, and diffusion of atomic and molecular hydrogen on the Fe-doped ZrCo (110) surface. It is found that the adsorption of H2 on doped surface seems thermodynamically more stable with more negative adsorption energy than that on the pure surface, and the dissociation energy of H2 on doped surface is much bigger therefore. However, compared with the pure system, there are fewer adsorption sites for spontaneous dissociation. After dissociation, the higher hydrogen adsorption strength sites would promote the H atom diffusion towards them where they can permeate into the bulk further. Furthermore, the ZrCo (110) surface possesses much higher hydrogen permeability and lower hydrogen diffusivity than its corresponding ZrCo bulk. Moreover, further comparison of the present results to analogous calculations for pure surface reveals that the Fe dopant facilitates the H2 molecule dissociation. Unfortunately, this does not improve the hydrogen storage performance of ZrCo alloy due to the H atom diffusion on the surface and into bulk are prevented with higher reaction energetic barriers by doping Fe. Consequently, ZrCo (110) surface modified with Fe atoms should not be preferred as a result of its terrible hydrogen permeability. A clear and deep comprehending of the inhibiting effect of Fe dopant on the hydrogen storage of ZrCo materials from the perspective of the surface adsorption of hydrogen are obtained from the present results.

Upper-neck irradiation (UNI) at the uninvolved neck has shown similar regional relapse-free survival as standard whole-neck irradiation (WNI) in N0-1 nasopharyngeal carcinoma patients. However, whether UNI at the contralateral uninvolved neck is feasible in unilateral N3 disease, defined as6 cm and/or below the caudal border of the cricoid cartilage, remains unclear.Data for 291 nasopharyngeal carcinoma patients with unilateral N3 disease, who were treated with intensity-modulated radiotherapy from 2009 to 2015, were retrospectively analyzed. Among them, 190 received bilateral WNI (WNI group); the remaining 101 received WNI at the involved neck and UNI at the contralateral uninvolved neck (UNI group). Survival rates were estimated using the Kaplan-Meier method and difference between groups were compared using the log rank tests.The median follow-up was 79.4 months (interquartile range, 56.0-89.3). Twenty-five patients had regional lymph node relapses (UNI: 10.9%, 11/101 vs. WNI: 7.4%, 14/190, p=0.31). Of these, 23 patients relapsed within the previously involved neck regions, while only two patients had relapses in the contralateral uninvolved neck (one each in the UNI and WNI groups). Five-year regional relapse-free survival rates were similar between groups (89.7% vs. 92.7%, p=0.29). Similar between-group findings were also observed for 5-year overall survival (76.1% vs. 80.4%, p=0.40), distant metastasis-free survival (74.9% vs. 79.2%, p=0.44), and local relapse-free survival (95.6% vs. 94.7%, p=0.64). Furthermore, oncologic outcomes in subgroup and multivariable analyses were similar between groups.Regional control and survival outcomes were comparable in UNI at the contralateral uninvolved neck and standard WNI in nasopharyngeal carcinoma patients with unilateral N3 disease. Our findings provide evidence for future radiotherapy guidelines of nasopharyngeal carcinoma.

Use of an LMA ProSeal™ laryngeal mask airway (P-LMA; Teleflex) with no neuromuscular block is considered a safe alternative to tracheal intubation in short-duration paediatric laparoscopic surgery. However, few studies have evaluated surgical conditions of short-duration paediatric laparoscopic surgery using this anaesthetic technique. We assessed surgical conditions for paediatric laparoscopic inguinal hernia repair using P-LMA with and without neuromuscular block.Sixty-six patients undergoing laparoscopic inguinal hernia repair were randomised to receive a neuromuscular block (train-of-four 1-2 twitches) using rocuronium or no neuromuscular block with the P-LMA. All operations were performed by the same surgeon who determined the surgical conditions using the Leiden-surgical rating scale (L-SRS). Secondary outcomes included perioperative data, haemodynamics, and adverse events.Neuromuscular block improved surgical conditions compared with no neuromuscular block: mean (standard deviation) L-SRS 4.1 (0.5) vs 3.5 (0.6), respectively (P0.0001). Mean rocuronium dose in the neuromuscular block group was 12.7 (4.4-29.7) mg or 0.7 (0.6-0.8) mg kgNeuromuscular block significantly improved surgical conditions and reduced the incidence of adverse events during surgery and anaesthesia when an LMA Proseal™ was used in short-duration paediatric laparoscopic surgery.ChiCTR2000038529.

Graphical abstract, Introduction A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. Objectives We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. Methods Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. Results We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. Conclusion This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

Tyrosinase (TYR) is an important polyphenolic oxidase enzyme and usually regards as a biomarker of melanoma cancer. Highly effective tracking TYR activity in vivo will help to study the mechanism of TYR in living organisms and forecasts related diseases. In this study, we present a novel TYR-activatable fluorescent probe (CHMC-DOPA) for tracking TYR activity in vitro and in vivo. CHMC-DOPA is constructed by incorporating dopamine (DOPA) moiety into a fluorescent chloro-hydroxyl-merocyanine (CHMC) scaffold. Upon exposure to TYR, the dopamine unit in CHMC-DOPA is oxidized to a dopaquinone derivative, and an intramolecular photo-induced electron transfer (PET) process between CHMC fluorophore and o-dopaquinone will take place, the fluorescence of CHMC-DOPA is quenched rapidly. Therefore, the evaluation of TYR activity is established in terms of the relationship between fluorescence quenching efficiency and TYR activity. In our experiments, CHMC-DOPA shows various advantages, such as fast response (8⬰min), low concentration of TYR activation (0.5 U/mL), good water-solubility, as well as the lowest detection limit (0.003 U/mL) compared with previously reported works. Furthermore, CHMC-DOPA also exhibits excellent cell membrane permeability and low cytotoxicity, which is successfully used to monitor endogenous TYR activity in living cancer cells and zebrafish models. CHMC-DOPA performs well, and we anticipate that this newly designed novel platform will provide an alternative for high effective monitoring TYR activity in biosystems.

As a natural abundant high-carbon resource, the use of coal to develop carbon nanomaterials is an important research topic. In recent years, a variety of carbon materials with different morphologies and nanotextures have been designed and constructed using coal and their derivatives as precursors, and their use in energy storage, catalysis, adsorption and absorption have been explored. State-of-the-art research on carbon nanomaterials derived from coals of different rank and their derivatives are summarized with specific attention to the synthesis strategies and structure control. The use of these coal-derived carbons for energy storage, such as secondary batteries and supercapacitors, is also discussed in terms of their structural features. The review aims to provide valuable insight into the present challenges and inspire new ideas for the development of advanced coal-derived carbon materials.